CN101744830B - Flavonoid compound and application of plant extract containing same - Google Patents
Flavonoid compound and application of plant extract containing same Download PDFInfo
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Abstract
Description
技术领域 technical field
本发明涉及一类黄酮类化合物或含其的植物提取物在医药领域中的新应用。The invention relates to a new application of a class of flavonoid compounds or plant extracts containing them in the field of medicine.
背景技术 Background technique
据不完全统计，目前我国丙肝抗体阳性患者有4000万人之多，其中80％会患上慢性丙肝。丙肝是经血液、性接触、母婴及日常生活接触等途径传播的一种肝脏疾病。感染HCV后，和HBV感染一样，易发生慢性肝炎、肝硬化和肝癌。According to incomplete statistics, there are as many as 40 million hepatitis C antibody-positive patients in my country, and 80% of them will suffer from chronic hepatitis C. Hepatitis C is a liver disease that is transmitted through blood, sexual contact, mother to child and daily life contact. After HCV infection, like HBV infection, chronic hepatitis, liver cirrhosis and liver cancer are prone to occur.
目前，主要使用长效干扰素联合利巴韦林治疗肝功正常的丙肝患者，总体持续病毒学应答率为52％。但干扰素和利巴韦林在治疗过程中，有可能出现骨髓抑制以及情感抑郁、消化道症状等不良反应。并且，长效干扰素价格昂贵，一个疗程48周需花费人民币6万元左右。因此开发抗HCV疗效好、价格低，副作用较小的天然药物是目前医药行业的一个热点。Currently, long-acting interferon combined with ribavirin is mainly used to treat hepatitis C patients with normal liver function, and the overall sustained virological response rate is 52%. However, during the treatment of interferon and ribavirin, adverse reactions such as bone marrow suppression, emotional depression, and gastrointestinal symptoms may occur. Moreover, long-acting interferon is expensive, and a 48-week course of treatment costs about RMB 60,000. Therefore, the development of natural medicines with good anti-HCV curative effect, low price and less side effects is a hot spot in the pharmaceutical industry at present.
黄酮类化合物泛指两个具有酚羟基的苯环(A-与B-环)通过中央三碳原子相互连接而成的一系列化合物(通式如下所示)。黄酮类化合物的主要结构类型有黄酮类、黄酮醇类、二氢黄酮类、二氢黄酮醇类、二氢异黄酮、查尔酮、花色素类等14种。(具体请见姚新生主编的《天然药物化学》，第四版，人民卫生出版社)Flavonoids generally refer to a series of compounds in which two benzene rings (A- and B-rings) with phenolic hydroxyl groups are connected to each other through the central three carbon atoms (the general formula is shown below). The main structural types of flavonoids are flavonoids, flavonols, dihydroflavonoids, dihydroflavonols, dihydroisoflavones, chalcones, anthocyanins, etc. 14 kinds. (For details, please refer to "Natural Medicinal Chemistry" edited by Yao Xinsheng, fourth edition, People's Health Publishing House)
发明内容 Contents of the invention
本发明所要解决的技术问题是提供一类黄酮类化合物或含其的植物提取物在制备抗丙型肝炎病毒药物中的新应用。The technical problem to be solved by the present invention is to provide a new application of a class of flavonoids or plant extracts containing them in the preparation of anti-hepatitis C virus drugs.
本发明人经研究，发现具有如式I所示的母核结构的一类黄酮类化合物具有较佳的抗丙型肝炎病毒活性。After research, the inventors found that a class of flavonoids with the core structure shown in formula I has better anti-hepatitis C virus activity.
式IFormula I
其中，R1、R2、R4、R5和R6独立地为H、OH或OMe，R3为H、OH、OMe或β-D-葡萄糖酸基，2位和3位碳之间为单键或双键。Among them, R 1 , R 2 , R 4 , R 5 and R 6 are independently H, OH or OMe, R 3 is H, OH, OMe or β-D-gluconic acid group, between the 2 and 3 carbon for single or double bonds.
较佳的，所述的黄酮类化合物为以下两种化合物中的任一种：Preferably, the flavonoids are any one of the following two compounds:
(1)(1)
式AFormula A
其中，R2、R5和R6独立地为H或OH，R3为OH或β-D-葡萄糖酸基，R4为氢；Wherein, R 2 , R 5 and R 6 are independently H or OH, R 3 is OH or β-D-gluconic acid group, R 4 is hydrogen;
(2)(2)
式HFormula H
其中，R1、R2、R3、R4和R5独立地为H、OH或OMe，其为外消旋化合物或手性化合物。Wherein, R 1 , R 2 , R 3 , R 4 and R 5 are independently H, OH or OMe, which are racemic compounds or chiral compounds.
本发明中，所述的如式A所示的黄酮类化合物优选下述三种化合物中的任一种：In the present invention, the flavonoid compound shown in formula A is preferably any one of the following three compounds:
(1)如式B所示的芹菜素，即式A化合物，其中R3和R5为OH，R2和R6为H，其分子式为C15H10O5；分子量270.25，化学名为5，7，4’-三羟基黄酮，英文名称为Apigenin，CAS编号为520-36-5。(1) Apigenin as shown in formula B, that is, a compound of formula A, wherein R 3 and R 5 are OH, R 2 and R 6 are H, and its molecular formula is C 15 H 10 O 5 ; molecular weight 270.25, chemical name 5,7,4'-Trihydroxyflavone, the English name is Apigenin, and the CAS number is 520-36-5.
式BFormula B
(2)如式C所示的木犀草素，即式A化合物，其中R3、R5和R6为OH，R2为H，其分子式为C15H10O6；分子量286.09，化学名为5，7，3′，4′-四羟基黄酮，英文名称为Luteolin，CAS编号为491-70-3。(2) Luteolin as shown in formula C, that is, a compound of formula A, wherein R 3 , R 5 and R 6 are OH, R 2 is H, and its molecular formula is C 15 H 10 O 6 ; molecular weight 286.09, chemical name It is 5,7,3′,4′-tetrahydroxyflavone, its English name is Luteolin, and its CAS number is 491-70-3.
式CFormula C
(3)如式D所示的黄芩苷，即式A化合物，其中R5和R6为H；R3为β-D-葡萄糖酸基，R2为OH，其分子式为C21H18O11；分子量446.35，化学名为化学名为β-D-葡萄糖酸-5，6-二羟基-4-O-2-苯基-4H-苯并吡喃-7，英文名称为Baicalin，CAS编号为21967-41-9。(3) Baicalin as shown in formula D, that is, the compound of formula A, wherein R 5 and R 6 are H; R 3 is β-D-gluconic acid group, R 2 is OH, and its molecular formula is C 21 H 18 O 11 ; molecular weight 446.35, chemical name is β-D-gluconic acid-5,6-dihydroxy-4-O-2-phenyl-4H-benzopyran-7, English name is Baicalin, CAS number for 21967-41-9.
式DFormula D
本发明中，所述的如式H所示的黄酮类化合物优选下述化合物E：In the present invention, the flavonoid compound shown in formula H is preferably the following compound E:
式EFormula E
其中，R1、R2、R3、R4和R5独立地为H、OH或OMe。Wherein, R 1 , R 2 , R 3 , R 4 and R 5 are independently H, OH or OMe.
所述的如式E所示的黄酮类化合物优选下述两种化合物中的任一种：The flavonoid compound shown in formula E is preferably any one of the following two compounds:
(1)如式F所示的柚皮素，即式E化合物，其中R1、R3和R5为OH，R2和R4为H，其分子式为C15H12O5；分子量272，化学名为(2S)-5，7，4’-三羟基二氢黄酮，英文名称为(2S)-Naringenin。(1) Naringenin as shown in formula F, that is, a compound of formula E, wherein R 1 , R 3 and R 5 are OH, R 2 and R 4 are H, and its molecular formula is C 15 H 12 O 5 ; molecular weight 272 , the chemical name is (2S)-5,7,4'-trihydroxydihydroflavone, and the English name is (2S)-Naringenin.
式FFormula F
(2)如式G所示的6-甲氧基柚皮素，即式E化合物，其中R1、R3和R5为OH，R2为OMe，R4为H，其分子式为C16H14O6；分子量302，化学名为(2S)-5，7，4’-三羟基-6-甲氧基二氢黄酮，英文名称为(2S)-6-methoxynaringenin。(2) 6-methoxynaringenin as shown in formula G, that is, the compound of formula E, wherein R 1 , R 3 and R 5 are OH, R 2 is OMe, R 4 is H, and its molecular formula is C 16 H 14 O 6 ; molecular weight 302, chemical name (2S)-5,7,4'-trihydroxy-6-methoxydihydroflavone, English name (2S)-6-methoxynaringenin.
式GFormula G
本发明中，所述的黄酮类化合物可由天然植物中提取，较佳的为夏枯草或半枝莲。本发明所述的黄酮类化合物不仅包括市售单体纯品，也包括从天然植物中提取的粗品或纯品，还包括以这些黄酮类化合物为有效成份的植物提取物。In the present invention, the flavonoids can be extracted from natural plants, preferably Prunella vulgaris or Scutellaria barbata. The flavonoids described in the present invention include not only commercially available monomer pure products, but also crude or pure products extracted from natural plants, and plant extracts with these flavonoids as active ingredients.
本发明的积极进步效果在于：本发明所述的黄酮类化合物具有较好的抗丙型肝炎病毒的作用，其副作用小，其来源于中药，廉价安全有效。The positive and progressive effect of the present invention lies in that the flavonoid compound described in the present invention has better anti-hepatitis C virus effect, has less side effects, is derived from traditional Chinese medicine, is cheap, safe and effective.
具体实施方式 Detailed ways
下面用实施例来进一步说明本发明，但本发明并不受其限制。The present invention is further illustrated below with examples, but the present invention is not limited thereto.
实施例中所用的芹菜素、木犀草素、黄芩苷柚皮素和6-甲氧基柚皮素购自上海中药标准化中心。HCV-E2抗体取自美国Scripps研究所。对照药物α干扰素以及其它所用试剂和原料均国内市售可得。Apigenin, luteolin, baicalin naringenin and 6-methoxynaringenin used in the examples were purchased from Shanghai Traditional Chinese Medicine Standardization Center. HCV-E2 antibody was obtained from Scripps Research Institute, USA. The control drug α-interferon and other reagents and raw materials used are all commercially available in China.
效果实施例体外细胞试验Effect Example In Vitro Cell Test
1、样品制备1. Sample preparation
用100％DMSO将样品溶解成浓度为20mg/ml的母液，4℃保存。检测时，再用100％DMSO将贮存母液分别稀释为5mg/ml和2mg/ml的溶液。The sample was dissolved in 100% DMSO to a mother solution with a concentration of 20 mg/ml, and stored at 4°C. When testing, the stock mother solution was diluted with 100% DMSO to 5 mg/ml and 2 mg/ml solutions respectively.
2、细胞、病毒及细胞培养2. Cell, virus and cell culture
本研究采用Huh7衍生细胞系和HCV病毒株(取自中国科学院上海巴斯德研究所)，该病毒株能在该细胞中产生高滴度、有感染能力的HCV病毒颗粒。This study used a Huh7-derived cell line and an HCV virus strain (obtained from the Institut Pasteur of Shanghai, Chinese Academy of Sciences), which can produce high-titer, infectious-competent HCV virus particles in the cells.
将细胞以1×104个/100μl/孔接种于96孔细胞培养板中，培养过夜。用完全培养基(DMEM中含10％胎牛血清，100U/ml青霉素，100μg/ml链霉素)将HCV病毒上清稀释到1×103ffu/ml，按50ffu/孔感染细胞。Cells were seeded in 96-well cell culture plates at 1×10 4 cells/100 μl/well and cultured overnight. Dilute the HCV viral supernatant to 1×10 3 ffu/ml with complete medium (10% fetal bovine serum in DMEM, 100 U/ml penicillin, 100 μg/ml streptomycin), and infect the cells at 50 ffu/well.
3、HCV病毒集落减少实验。3. HCV virus colony reduction experiment.
将不同浓度(5mg/ml和2mg/ml)的样品溶液分别以体积比1∶50的比例稀释于完全培养基中，使之浓度相应为100μg/ml和40μg/ml，分别吸取适量样品溶液与等体积病毒稀释液混和均匀，制备成浓度为50μg/ml和20μg/ml的样品。室温孵育1小时。弃去96孔细胞培养板中的培养基，每孔加入100μl上述混和液，置37℃、5％CO2培养箱中培养8小时。弃去上清，用无钙镁离子的磷酸盐缓冲液(DPBS)洗1次，每孔加入150μl新鲜的完全培养基，置37℃、5％CO2培养箱中培养64小时。每孔加入150μl 4％多聚甲醛(PFA)，室温固定15分钟。弃去上清，用DPBS洗涤3次，用抗HCV-E2人源单克隆抗体和免疫荧光素标记的抗人二抗(取自中国科学院上海巴斯德研究所)进行免疫荧光染色。荧光显微镜观察记录病毒集落数量。Dilute sample solutions with different concentrations (5mg/ml and 2mg/ml) in the complete culture medium at a ratio of 1:50 by volume, so that the concentrations are 100μg/ml and 40μg/ml respectively, draw appropriate amount of sample solution and Equal volumes of virus diluents were mixed evenly to prepare samples with concentrations of 50 μg/ml and 20 μg/ml. Incubate for 1 hour at room temperature. Discard the medium in the 96-well cell culture plate, add 100 μl of the above mixed solution to each well, and culture in a 37° C., 5% CO 2 incubator for 8 hours. Discard the supernatant, wash once with calcium and magnesium ion-free phosphate buffered saline (DPBS), add 150 μl of fresh complete medium to each well, and culture in a 37°C, 5% CO2 incubator for 64 hours. Add 150 μl of 4% paraformaldehyde (PFA) to each well and fix at room temperature for 15 minutes. The supernatant was discarded, washed 3 times with DPBS, and immunofluorescent staining was performed with anti-HCV-E2 human monoclonal antibody and immunofluorescence-labeled anti-human secondary antibody (obtained from Shanghai Pasteur Institute, Chinese Academy of Sciences). The number of virus colonies was recorded by fluorescence microscopy.
4、阴性对照组设定。4. Negative control group setting.
阴性对照组以DMSO代替样品溶液，其余同样品检测。In the negative control group, DMSO was used to replace the sample solution, and the rest were tested with the same sample.
5、α干扰素对照组设定。5. Interferon-alpha control group setting.
用完全培养基将干扰素溶液分别稀释至5，50，500IU/ml。与细胞孵育1小时，加入病毒稀释液，其余同提取物检测。Dilute the interferon solution to 5, 50, and 500 IU/ml with complete medium. Incubate with the cells for 1 hour, add virus diluent, and detect the rest with the extract.
抑制率＝(阴性对照组病毒集落数量-实验组的病毒集落数量)/阴性对照组病毒集落数量×100％Inhibition rate=(the number of virus colonies in the negative control group-the number of virus colonies in the experimental group)/the number of virus colonies in the negative control group×100%
实验结果Experimental results
其中，柚皮素即为本发明的式F化合物，6-甲氧基柚皮素即为本发明的式G化合物。Wherein, naringenin is the compound of formula F of the present invention, and 6-methoxynaringenin is the compound of formula G of the present invention.
细胞毒性说明：Cytotoxicity Statement:
无细胞毒性＝实验组细胞密度/阴性对照组细胞密度≥80％No cytotoxicity = cell density of experimental group/cell density of negative control group ≥ 80%
有细胞毒性＝实验组细胞密度/阴性对照组细胞密度＜80％Cytotoxicity = cell density of experimental group / cell density of negative control group < 80%
实验结果显示芹菜素、木犀草素、黄芩苷、柚皮素和6-甲氧基柚皮素等黄酮类化合物对丙型肝炎病毒有显著的抑制作用。Experimental results show that flavonoids such as apigenin, luteolin, baicalin, naringenin and 6-methoxynaringenin have significant inhibitory effects on hepatitis C virus.
综上所述，各项实验结果表明芹菜素、木犀草素、黄芩苷、柚皮素和6-甲氧基柚皮素等黄酮类化合物具有抗丙型肝炎病毒活性。In summary, the experimental results show that flavonoids such as apigenin, luteolin, baicalin, naringenin and 6-methoxynaringenin have anti-HCV activity.
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